Abstract
Cortical precursor cells secrete soluble factors for their own survival and self-renewal. We show here that neural precursor cells isolated from embryonic rat cortices abundantly secrete leukemia inhibitory factor (LIF) and express its receptor components, gp130 and LIF receptor. LIF signaling is responsible for cortical precursor cell survival. As described previously, LIF caused astrocytic differentiation of cultured embryonic cortical precursor cells. LIF-mediated survival and astrocytic differentiation of cortical precursor cells were differentially regulated, depending on the developmental ages of embryos from which cortical precursors were isolated. LIF did not enhance the survival of cortical precursor cells isolated from later embryos (embryonic day 16, E16). Moreover, LIF-mediated astrocytic differentiation was not observed in early (E12) cortical precursors. Inhibition studies revealed that Janus-activated kinase/signal transducer and activator of transcription and phosphatidylinositol 3 kinase/Akt pathways participate in both the LIF-mediated effects. However, mitogen-activated protein kinase, another signal pathway activated by LIF, was specifically responsible for astrocytic differentiation. These findings collectively indicate that precursor cells self-regulate the sequential processes of brain development, such as early maintenance of the precursor cell population and later differentiation into astrocytes, via common LIF signaling.
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Abbreviations
- LIF:
-
leukemia inhibitory factor
- LIFR:
-
LIF receptor
- E12–16:
-
embryonic day 12–16
- JAK/STAT:
-
Janus-activated kinase/signal transducer and activator of transcription
- PI3K/Akt:
-
phosphatidylinositol 3 kinase/Akt
- MAPK:
-
mitogen-activated protein kinase
- gp130:
-
glycoprotein 130
- CNS:
-
central nervous system
- CNTF:
-
ciliary neurotrophic factor
- SCM:
-
stem cell-conditioned medium
- bFGF:
-
basic fibroblast growth factor
- TuJ1:
-
β-tubulin type III
- GFAP:
-
glial fibrillary acidic protein
- DIV:
-
day in vitro
- EGF:
-
epidermal growth factor
- BrdU:
-
bromodeoxyuridine
- LDH:
-
lactate dehydrogenase
- N-CoR:
-
nuclear receptor co-repressor
- HBSS:
-
Hank's balanced salt solution
- EtBr:
-
ethidium bromide.
References
Chang MY, Park CH and Lee SH (2003) Embryonic cortical stem cells secrete diffusible factors to enhance their survival. Neuroreport 14: 1191–1195
Kilpatrick TJ, Richards LJ and Bartlett PF (1995) The regulation of neural precursor cells within the mammalian brain. Mol. Cell. Neurosci. 6: 2–15
Sommer L and Rao M (2002) Neural stem cells and regulation of cell number. Prog. Neurobiol. 66: 1–18
Bayer SA and Altman J (1991) Neocortical Development. New York: Raven Press
Kilpatrick TJ and Bartlett PF (1993) Cloning and growth of multipotential neural precursors: requirements for proliferation and differentiation. Neuron 10: 255–265
Taupin P, Ray J, Fischer WH, Suhr ST, Hakansson K, Grubb A and Gage FH (2000) FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor. Neuron 28: 385–397
Chang MY, Son H, Lee YS and Lee SH (2003) Neurons and astrocytes secrete factors that cause stem cells to differentiate into neurons and astrocytes, respectively. Mol. Cell. Neurosci. 23: 414–426
Temple S and Davis AA (1994) Isolated rat cortical progenitor cells are maintained in division in vitro by membrane-associated factors. Development 120: 999–1008
Tsai RYL and McKay RDG (2000) Cell contact regulates fate choice by cortical stem cells. J. Neurosci. 20: 3725–3735
Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA and Temple S (2000) Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28: 69–80
Turnley AM and Bartlett PF (2000) Cytokines that signal through the leukemia inhibitory factor receptor-β complex in the nervous system. J. Neurochem. 74: 889–899
Murphy M, Dutton R, Koblar S, Cheema S and Bartlett P (1997) Cytokines which signal through the LIF receptor and their actions in the nervous system. Prog. Neurobiol. 52: 355–378
Mi H and Barres BA (1999) Purification and characterization of astrocyte precursor cells in the developing rat optic nerve. J. Neurosci. 19: 1049–1061
Mayer M, Bhakoo K and Noble M (1994) Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development 120: 143–153
Hughes SM, Lillien LE, Raff MC, Rohrer H and Sendtner M (1988) Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture. Nature 335: 70–73
Johe KK, Hazel TG, Muller T, Dugich-Djordjevic MM and McKay RD (1996) Single factors direct the differentiation of stem cells from the embryonic and the adult central nervous system. Genes Dev. 10: 3129–3140
Yanagisawa M, Nakashima K and Taga T (1999) STAT3-mediated astrocyte differentiation from mouse embryonic neuroepithelial cells by mouse oncostatin M. Neurosci. Lett. 269: 169–172
Shimazaki T, Shingo T and Weiss S (2001) The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural precursor cells. J. Neurosci. 21: 7642–7653
Hatta T, Moriyama K, Nakashima K, Taga T and Otani H (2002) The role of gp130 in cerebral cortical development: In vivo functional analysis in a mouse Exo Utero syprecursor. J. Neurosci. 22: 5516–5524
Schooltink H, Schmitz-Van de Leur H, Heinrich PC and Rose-John S (1992) Up-regulation of the interleukin-6-signal transducing protein (gp130) by interleukin-6 and dexamethasone in HepG2 cells. FEBS Lett. 297: 263–265
Rumajogee P, Madeira A, Verge D, Hamon M and Miquel MC (2002) Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share TrkB-dependent mechanisms. J. Neurochem. 83: 1525–1528
Hayashi H, Ishisaki A and Imamura T (2003) Smad mediates BMP-2-induced upregulation of FGF-evoked PC12 cell differentiation. FEBS Lett. 11: 30–34
Molne M, Studer L, Tabar V, Ting YT, Eiden MV and McKay RDG (2000) Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J. Neurosci. Res. 59: 301–311
Raff MC, Miller RH and Nobel N (1983) A glial progenitor cell that develops in vitro into an astrocyte or oligodendrocyte depending on culture medium. Nature 303: 390–396
Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K and Hirano T (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5: 449–460
Chen RH, Chang MC, Su YH, Tsai YT and Kuo ML (1999) Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phophatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J. Biol. Chem. 274: 23013–23019
Kim H and Baumann H (1999) Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol. Cell. Biol. 19: 5326–5338
Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C and Levitzki A (1991) Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J. Med. Chem. 34: 1896–1907
Alessi DR, Cuenda A, Cohen P, Dudley DT and Saltiel AR (1995) PD 98059 is a specific inhibitor of the activation of mitogen activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270: 27489–27494
Vlahos CJ, Matter WF, Hui KY and Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002). J. Biol. Chem. 269: 5241–5248
Nakashima K, Yanagisawa M, Arakawa H and Taga T (1999) Astrocyte differentiation mediated by LIF in cooperation with BMP2. FEBS Lett. 457: 43–46
Dittrich E, Haft CR, Muys L, Heinrich PC and Graeve L (1996) A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor. J. Biol. Chem. 271: 5487–5494
Gerhartz C, Dittrich E, Stoyan T, Rose-John S, Yasukawa K, Heirich PC and Graeve L (1994) Biosynthesis and half-life of the interleukin-6 receptor and its signal transducer gp130. Eur. J. Biochem. 223: 265–274
O'Brien CA and Manolagas SC (1997) Isolation and characterization of the human gp130 promoter. J. Biol. Chem. 272: 15003–15010
Blanchard F, Wang Y, Kinzie E, Duplomb L, Godard A and Baumann H (2001) Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor á, and oncostatin M receptor â by distinct mechanism. J. Biol. Chem. 276: 47038–47045
Bauer S, Rasika S, Jing Han, Mauduit C, Raccurt M, Morel G, Jourdan F, Benahmed M, Moyse E and Patterson PH (2003) Leukemia inhibitory factor is a key signal for injury-induced neurogenesis in the adult mouse olfactory epithelium. J. Neurosci. 23: 1792–1803
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM and Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703–716
Imura T, Kornblum HI and Sofroniew MV (2003) The predominant neural stem cell isolated from postnatal and adult forebrain but not early embryonic forebrain expresses GFAP. J. Neurosci. 23: 2824–2832
Ruffini F, Blain M and Antel JP (2003) In: Comparison of in vitro properties of adult and fetal human brain-derived glial progenitor cells. Meeting for the Society for Neuroscience, November 2003
Rane SG and Reddy EP (2000) Janus kinase: components of multiple signaling pathways. Oncogene 19: 5662–5679
Stahl N and Yancopoulos GD (1994) The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines. J. Neurobiol. 25: 1454–1466
Dolcet X, Soler RM, Gould TW, Egea J, Oppenheim RW and Comella JX (2001) Cytokine promote motor neuron survival through the Janus Kinase-dependent activation of the phosphatidylinositol 3-kinase pathway. Mol. Cell. Neurosci. 18: 619–631
Alonzi T, Middleton G, Wyatt S, Buchman V, Betz UAK, Muller W, Musiani P, Poli V and Davies AM (2001) Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons. Mol. Cell. Neurosci. 18: 270–282
Shen S, Wiemelt AP, McMorris FA and Barres BA (1999) Retinal ganglion cells lose trophic responsiveness after axotomy. Neuron 23: 285–295
Skaper SD, Floreani M, Negro A, Facci L and Giusti P (1998) Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J. Neurochem. 70: 1859–1868
Anderson CNG and Tolkovsky AM (1999) A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J. Neurosci. 19: 664–673
Hetman M, Kanning K, Cavanaugh JE and Xia Z (1999) Neuroprotection by brain-derived neurotropic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 274: 22569–22580
Bonni A, Brunet A, West A E, Datta SR, Takasu MA and Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286: 1358–1362
Atwal JK, Massie B, Miller FD and Kaplan DR (2000) The TrkB-Shc site signals neuronal survival and local axon growth via MEK and PI3-kinase. Neuron 27: 265–277
Dolcet X, Egea J, Soler RM, Martin-Zanca D and Comella JX (1999) Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival. J. Neurochem. 73: 521–531
Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR and Greenberg ME (1997) Regulation of neuronal survival by the serine–threonine protein kinase Akt. Science 275: 661–665
Packham G, White EL, Eischen CM, Yang H, Parganas E, Ihle JN, Grillot DA, Zambetti GP, Nunez G and Cleveland JL (1998) Selective regulation of Bcl-xL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. Genes Dev. 12: 2475–2487
Bonni A, Yi S, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD and Greenberg ME (1997) Regulation of gliogenesis in the central nervous system by the JAK/STAT signaling pathway. Science 278: 477–483
Rajan P and McKay RD (1998) Multiple routes to astrocytic differentiation in the CNS. J. Neurosci. 18: 3620–3629
Hermanson O, Jepsen K and Rosenfeld MG (2002) N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419: 934–939
Sakakibara S, Nakamura Y, Satoh H and Okano H (2001) RNA-binding protein Musashi2: developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS. J. Neurosci. 21: 8091–8107
Acknowledgements
This work was supported by NRL Grant M1-0318-00-0290 from the Korea Institute of S&T Evaluation and Planning.
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Chang, MY., Park, CH., Son, H. et al. Developmental stage-dependent self-regulation of embryonic cortical precursor cell survival and differentiation by leukemia inhibitory factor. Cell Death Differ 11, 985–996 (2004). https://doi.org/10.1038/sj.cdd.4401426
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DOI: https://doi.org/10.1038/sj.cdd.4401426
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